Valproic Acid in Treating Young Patients With Recurrent or Refractory Solid Tumors or CNS Tumors

A Phase I Study of Valproic Acid in Children With Recurrent/Progressive Solid Tumors Including CNS Tumors

RATIONALE: Drugs used in chemotherapy, such as valproic acid, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Valproic acid may also stop the growth of solid tumors or CNS tumors by blocking blood flow to the tumor.

PURPOSE: This phase I trial is studying the side effects and best dose of valproic acid in treating patients with recurrent or refractory solid tumors or CNS tumors.

Study Overview

• Status: Completed
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific; Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: valproic acid

Detailed Description

OBJECTIVES:

Primary

• Determine the toxic effects of valproic acid (VPA) administered at doses required to maintain serum trough VPA concentrations of 100-150 mcg/mL or 150-200 mcg/mL in young patients with recurrent or refractory solid tumors or CNS tumors.

Secondary

• Determine the steady-state serum trough concentration of free and total VPA at the targeted total trough VPA concentration in these patients.
• Determine the steady state histone acetylation status of peripheral blood monocytes at the targeted trough VPA concentration in these patients.
• Determine the pharmacokinetic profile of this drug in these patients.
• Correlate histone acetylation with free or total trough VPA concentration in these patients.
• Determine, preliminarily, the antitumor activity of this drug in these patients.

OUTLINE: This is a dose-escalation, multicenter study.

For course 1, patients receive escalating doses of oral valproic acid (VPA) twice daily until a target serum trough VPA concentration range is maintained for 28 days. Patients who achieve the target serum trough VPA concentration range receive subsequent courses of oral VPA twice daily (at the dose found to maintain the target serum trough VPA concentration range) on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

The first cohort of 6 patients receives VPA to achieve an initial target trough serum VPA concentration. If fewer than 2 of 6 patients in the first cohort experience dose-limiting toxicity (DLT), then a second cohort of 6 patients receives VPA to achieve the next higher target trough serum VPA concentration. If fewer than 2 patients from the second cohort experience DTL, then 6 additional patients are enrolled in this cohort to better define pharmacokinetics and DLT at this VPA concentration range.

After completion of study treatment, patients are followed annually.

PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hôpital Sainte Justine
• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Stanford, California, United States, 94305
      • Stanford Comprehensive Cancer Center - Stanford
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Children's Hospital - Fairview
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University Cancer Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030-2399
      • Baylor University Medical Center - Houston
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed* malignant solid tumor, including CNS tumors, at original diagnosis or relapse

  • Recurrent or refractory disease NOTE: *Histologic confirmation not required for intrinsic brain stem or optic pathway tumors

• Measurable or evaluable disease, defined by 1 of the following criteria:

  • Any unidimensionally measurable lesion ≥ 10 mm by standard MRI or CT scan for either solid or CNS tumors
  • At least 1 nonmeasurable lesion that is evaluable by nuclear medicine, immunocytochemistry, tumor markers, cerebrospinal fluid cytology, or other reliable measures
• No known curative therapy exists
• No documented tumor involvement in the bone marrow

PATIENT CHARACTERISTICS:

Age

• 2 to 21

Performance status*

• Lansky 50-100% (for patients ≤ 10 years of age)
• Karnofsky 50-100% (for patients > 10 years of age)

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3 (transfusion independent)
• Hemoglobin ≥ 8.0 g/dL (transfusions allowed)

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT ≤ 110 (ULN for this study is 45 U/L)
• Albumin ≥ 2 g/dL

Renal

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR

• Creatinine based on age as follows:

  • No greater than 0.8 mg/dL (for patients ≤ 5 years of age)
  • No greater than 1.0 mg/dL (for patients 6 to 10 years of age)
  • No greater than 1.2 mg/dL (for patients 11 to 15 years of age)
  • No greater than 1.5 mg/dL (for patients over 15 years of age)

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Neurologic deficits in patients with CNS tumors must be stable for ≥ 1 week before study entry
• No uncontrolled infection
• No known urea cycle disorders or other metabolic disorders
• No other condition that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Recovered from prior immunotherapy
• At least 7 days since prior hematopoietic growth factors that support platelet or WBC number or function
• At least 7 days since prior antineoplastic biologic agents

• At least 3 months since prior stem cell transplantation or rescue without total body irradiation

  • No evidence of active graft vs host disease
• No other concurrent anticancer biologic therapy or immunotherapy

Chemotherapy

• More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered
• No other concurrent anticancer chemotherapy

Endocrine therapy

• Patients with CNS tumors must be on a stable or decreasing dose of dexamethasone for the past 7 days

Radiotherapy

• See Biologic therapy
• Recovered from prior radiotherapy
• At least 6 months since prior total body irradiation, craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis
• At least 6 weeks since other prior substantial bone marrow radiotherapy
• At least 2 weeks since prior local palliative small port radiotherapy
• No concurrent anticancer radiotherapy

Surgery

• Not specified

Other

• No other concurrent investigational agents
• No other concurrent anticancer agents

• No other concurrent anticonvulsants

  • Patients receiving valproic acid (VPA) before study entry must have a total trough VPA concentration < 100 mcg/mL within the past 7 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment 1; VPA Target Trough Concentration 75-100 mcg/mL, week 1 VPA dose: 15 mg/kg/day, divided tid	Drug: valproic acid
EXPERIMENTAL: Treatment 10; VPA Target Trough Concentration 100-150 mcg/mL, week 1 VPA dose: 15 mg/kg/day, divided tid	Drug: valproic acid
EXPERIMENTAL: Treatment 20; VPA Target Trough Concentration 150-200 mcg/mL	Drug: valproic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Efficacy of oral etoposide at 50 mg/m2/day given concurrently with radiotherapy

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Jack M. Su, MD, Texas Children's Cancer Center; Study Chair: Heidi V. Russell, MD, Texas Children's Cancer Center

Publications and helpful links

General Publications

• Su JM, Li XN, Thompson P, Ou CN, Ingle AM, Russell H, Lau CC, Adamson PC, Blaney SM. Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children's oncology group report. Clin Cancer Res. 2011 Feb 1;17(3):589-97. doi: 10.1158/1078-0432.CCR-10-0738. Epub 2010 Nov 29.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (ACTUAL): October 1, 2007
• Study Completion (ACTUAL): March 1, 2012

Study Registration Dates

• First Submitted: April 5, 2005
• First Submitted That Met QC Criteria: April 5, 2005
• First Posted (ESTIMATE): April 6, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): August 7, 2014
• Last Update Submitted That Met QC Criteria: August 6, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: unspecified childhood solid tumor, protocol specific; childhood high-grade cerebral astrocytoma; childhood infratentorial ependymoma; childhood supratentorial ependymoma; recurrent childhood supratentorial primitive neuroectodermal tumor; recurrent childhood cerebellar astrocytoma; recurrent childhood cerebral astrocytoma; recurrent childhood ependymoma; recurrent childhood brain tumor; recurrent childhood brain stem glioma; recurrent childhood medulloblastoma; recurrent childhood visual pathway and hypothalamic glioma; childhood craniopharyngioma; childhood central nervous system germ cell tumor; childhood grade I meningioma; childhood grade II meningioma; childhood grade III meningioma; childhood low-grade cerebral astrocytoma; childhood spinal cord neoplasm
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Site; Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: ADVL0419; COG-ADVL0419 (OTHER: Children's Oncology Group); NCI-05-C-0235; NCI-P6631; CDR0000417845 (OTHER: Clinical Trials.gov)